ProjectSummary/Abstract Treatmentoptionsthateffectivelycurepatientsdiagnosedwithacutemyeloidleukemia(AML)continueto representanareaofunmetneedinoncologyclinicalcare.WhileremissionratesinAMLpatientscanreach upwardsof80%underthecurrentfrontlinetherapyparadigm,nearlyallpatientsrelapsewithtreatment refractorydiseaselessthan5yearsafterdiagnosis.Relapsedrivenbytherapyresistantcellsthatpersistinthe bodyaftertreatment(definedasminimalresidualdisease)istheprincipalsourceoffatalityinAMLpatients. Therefore,understandinghowandwheretheseleukemiccellssurvivetreatmentinvivomayhelpadvancethe rationaldevelopmentofhighlysynergisticcombinationtherapiesforthetreatmentofAML.Usingafunctional genomicapproach(invivoRNAi)andanewmousemodelofAMLchemoresistance(ChemoR)generatedin ourlabs,wehaveidentifiedseveralputativemediatorsoftherapyresistance.Transcriptionalprofilingofthe ChemoRmodelallowedustogenerateachemoresistancegenesignaturethatweoverlappedwiththeresults oftheshRNAscreentoidentifyhigh-confidencegenesofinterest.Thetopgenesfromarankedlistofthemost highlyoverexpressedgenesinChemoRcellsandthetopdepletedgenesfromtheshRNAscreeninthecontext oftherapytreatmentwereselectedashighinteresthitsandsubsequentlytaggedforindividualfollow-up experiments.OneofthemosthighlyratedgenesonthatlistencodestheLiverKinaseB1(Lkb1)activator Strad?(STE20-relatedkinaseadaptoralpha),suggestingthatthisgenemayrepresentanuncharacterized therapeutictargetthatpromotesAMLresistance. ThegoalsofthisprojectaretoinvestigatewhatroleStrad?playsinhumanAMLchemoresistanceand todissecttheputativeresistancemechanismmediatedbythisgene. ToaddressthisquestionIproposeto: 1. AddresstheroleofSTRAD?inhumanAMLresponsetofrontlinechemotherapy. 2. CharacterizethebasicdrugresistancemechanismmediatedbyStrad?inAML. Byaddressingtheseaims,IcangaininsightintowhetherincreasedsignalingthroughSTRAD?representsa novelgeneticliabilityofAMLsinthecontextoffrontlinetherapythatcanbeexploitedtobettertreatthis disease.Workonthisprojectwillalsofostermydevelopmentasanindependentphysician-scientistbyplacing meattheinterfacebetweenclinicalandbasicscienceinvestigators.Sinceacriticalcomponentofthisworkis todeterminewhetherSTRAD?isbiologicallyrelevantinhumanAMLchemoresistance,Iwilllearnhowto translatebasicscienceobservationsgeneratedfromhypothesisdrivenexperimentsintopotentialtherapeutic strategiesthatcouldbeappliedclinicallytopotentiatetheeffectsoffrontlineagents.Ultimately,workingonthis projectwilltrainmeintheoverallapproachforaddressingkeytranslationalquestionsIwillfocusonlaterinmy career.